It is widely acknowledged that the normal development of the prostate gland as well as its hypertrophic growth is strongly dependent on androgens. There is abundant evidence that 5 alpha-dihydrotestosterone (DHT) is the active androgen in the prostate gland and mediates hormonal action. DHT is formed from testosterone by a 5 alpha-reductase. We have studied this conversion in vitro and have found structural analogs of testosterone which are effective inhibitors of DHT synthesis. The proposed study is to evaluate the effects of these inhibitors on actively growing prostatic tissue. One phase of the research plan is to continue screening steroid compounds for 5 alpha-reductase inhibitory activity. We have previously determined the structural characteristics for maximum inhibition. These are a 3 keto delta 4 configuration, 17 beta but no 17 alpha-substituents and few other modifications in the steroid nucleus. The successful inhibitors will then be tested in organ cultures of prostatic tissue. It has been shown and we have confirmed that testosterone and other androgens cause a marked epithelial hyperplasia in prostatic explants after several days of culture. We will attempt to suppress these and other androgenic manifestations by the inclusion of the DHT inhibitors in the culture medium. The metabolism of radioactive testosterone by the explants will be studied in the presence of effective inhibitors. Various kinds of prostatic tissue will be cultured: human carcinomatous and hyperplastic prostate, experimental prostate tumors from Copenhagen rats, and normal rat carcinomas. The efficacy of the DHT inhibitors in arresting existing tumors and in preventing the establishment of new ones will be evaluated. We will also study the uptake of exogenous testosterone by normal and carcinomatous prostatic tumors following the administration of various DHT inhibitors.